Method for real time monitoring of blood volume in a filter

ABSTRACT

A method and apparatus for monitoring and measuring the filter blood volume by dilution techniques in real time, wherein the filter may be in use or off line during the measurements. The system includes a method and apparatus for measuring or monitoring the volume of a blood side of a filter by employing one of a bolus in the blood side upstream of the filter; a change of the filtration rate in the filter; and a bolus on the dialysate side, wherein the filter blood volume is calculated from the obtained data.

FIELD OF THE INVENTION

[0001] The present invention relates to the real time measurement of afluid volume in a blood filter, and more particularly to measurements ofblood volume and changes in blood volume in a filter.

BACKGROUND OF THE INVENTION

[0002] In a large number of medical procedures, at least a portion ofthe blood volume is passed through a filter. The filter is designed toremove certain particulate matter from the blood. Alternatively, thefilter may be designed to remove specific chemicals and water solutionsduring the filtering process.

[0003] A typical device that exposes blood to a filter is a dialyzer.One of the main parameters of filter quality is filter blood volume(FBV). In terms of the dialyzer, the filter blood volume is oftenreferred to as dialyzer blood volume (DBV). Alternatively, the volumehas been referred to as fiber bundle volume. The term filter bloodvolume (FBV) will be used to encompass all the filter constructionsincluding filters having plates, fibers or biological cells.

[0004] Due to the exposure to the blood, clotting may occur in thefilter and thereby significantly decrease the surface area of exchangeavailable to the blood and hence decrease filtration. In this case thequality of treatment may be jeopardized. Fiber clotting duringhemodialysis can significantly decrease the volume of blood for soluteexchange.

[0005] Filter bundle volume, the total space within the bloodcompartment of hollow fiber hemodialyzers, correlates closely withdialyzer surface area, a major determinant of solute clearance. Adecrease in surface area due to clotting causes a decrease in soluteclearance that puts the patient at risk for inadequate dialysis. SinceFBV correlates with membrane surface area and is easy to measure invitro, FBV has been selected, in centers where dialyzer reuse ispermitted, as the main criterion that allows a dialyzer to be reused. Incountries where reuse of dialyzers is permitted, the main criteria forreuse is comparison of current FBV to its initial value. Traditionally,FBV is measured after cleaning, clot removal, and pressure flushing. TheFBV values determined by this traditional process may not represent theactual FBV.

[0006] The sequence of procedures for dialyzer reuse consists ofcleaning, including flushing the fibers with pressurized water to removeclots and debris, and measurement of FBV by volumetric displacement ofair or liquid which is compared with the original dialyzer volume.Because vigorous flushing removes much of the clot, FBV measured invitro may not represent the true in vivo volume and the correspondingsurface area available for solute exchange.

[0007] As the filters must be monitored and changed, the filters areusually disposed extracorporeal. The relationship of a filter to aparticular medical procedure is sensitive to a variety of parameters.Generally, the operating pressure, or resistance of a filter must bewithin particular predetermined limits.

[0008] However, as the filter is often removing material that is notperceptible to the naked eye, it is general practice to remove thefilter from the fluid circuit and fill the filter with water todetermine the filter volume. This process is not only time consuming,but exposes the filter to contamination. Also, the interruption of thefiltering process can be detrimental to the treatment of the patient.For example, in procedures such as hemodialysis, a filter is used toremove selected particles and liquids from the bloodstream of thepatient.

[0009] Difficulties in making such measurements have resulted from thefact that such procedures usually involve extracorporeal circulation ofthe blood from a patient through, for example a blood treatment system,and in many cases the effects of the system itself on the blood flow oron the measurement devices is unknown. For example, if blood is directedto a dialysis filter through plastic tubing, the effect of the plasticmaterial on measuring equipment using ultrasound waves may not be knownwith any certainty, since characteristics of the material can vary fromone tube to another.

[0010] There is emerging technology of locating a blood filter insidethe patient. However, even these filters are subject to the traditionalconcerns of proper functioning. If the filter is inserted into the body,then the measurements are made using sensors mounted on a blood vessel.

[0011] Therefore, the need exists for a method and apparatus formonitoring the FBV. A need also exists for the real time monitoring FBV.A need further exists for measuring the FBV during use or when thefilter is not in use, wherein the FBV volume has improved accuracy. Theneed also exists for monitoring a change in the FBV to allow adjustmentsto the procedures to accommodate or correct such volume changes.

SUMMARY OF THE INVENTION

[0012] It is an object of the present invention to provide a method andapparatus for accurately and reliably measuring filter blood volume in afilter. The filter may be a patient filter in the patient,extracorporeal, in a separate machine, dialyzer, or in a testingprocedure of the filter in a separate machine, such as a reuse machine.In the separate testing procedures, the FBV be determined with anyliquid. Therefore, blood not is required to determine the FBV. Thepresent invention also allows for FBV determination and particularlyexternally of the vein or artery, or in tubing leading to a bloodtreatment system which carries the blood exteriorly of the body of thepatient.

[0013] It is another object of the present invention to measure a filterblood volume by measuring an induced dilution in the blood andmonitoring passage of the dilution.

[0014] Generally, the present invention relates to a method andapparatus for measuring or monitoring the volume of a blood side of afilter by one of (i) employing a bolus injection in the blood sideupstream of the filter; (ii) changing the filtration rate in the filter,or (iii) employing a bolus injection in the dialysate side.

[0015] Briefly, in the bolus injection configuration, a bolus isintroduced in the blood side upstream of the filter during operation ofthe filter. A downstream signal corresponding to passage of the bolusdownstream of the filter is obtained. Further, a blood flow rate throughthe filter determined. Finally, the blood volume of the filter iscalculated in response to the downstream signal and the determined bloodflow rate. In a preferred embodiment, the bolus is introduced in theblood side upstream of the filter sufficiently near the filter tosubstantially preclude compensation of the downstream signal.

[0016] In the filtration rate change embodiment for monitoring of avolume of blood in a dialysis blood filter during operation of thefilter, a blood parameter is measured downstream of a blood side of thefilter; a blood flow rate through the blood side of the filter isdetermined; the filtration rate is changed to change the bloodparameter; and the blood volume is calculated in response to the changeof the blood parameter and the determined blood flow rate.

[0017] In the bolus injection in the dialysate side embodiment, thefilter blood volume is calculated from the introduction and passage of adiffusable and non diffusable indicator through the blood volume and thedialysate volume.

[0018] The present invention includes, in part, injecting a volume of adiffusable indicator into a blood flow, wherein the diluting effect ofthe indicator over a period of time is accurately determined by asensor, and these changes can be used to calculate the blood volume. Thesensor is positioned downstream of the injection so that the indicatorpasses the sensor, with the measured diluting effect being used todetermine various blood parameters. The present invention may employ therelationship between the velocity of ultrasound in blood and theconstituents of the blood. That is, the velocity of ultrasound in bloodis a function of, among other things, the proteins and ions contained inthe blood, with the sound velocity increasing with an increase inprotein concentration. Accordingly, the velocity of sound through ablood sample can be varied by diluting the blood with an indicatorhaving different acoustical characteristics than those of the blood; forexample, through the use of a saline solution that has no proteins.

[0019] The present invention provides a relatively simple technology formeasuring the volume of a blood filter and creates an opportunity tocontrol filter and dialyzer performance and give an early warning ofclotting to improve the quality of a variety of procedures includinghemodialysis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]FIG. 1 is a system view of a filter incorporated in a circulationsystem and an apparatus for measuring filter blood volume.

[0021]FIG. 2 is a set of the dilution curves recorded by an arterial(pre-filter) ultrasound sensor and a venous (post-filter) sensorfollowing an injection of a bolus into the arterial (filter inflow)blood line.

[0022]FIG. 3 is a schematic showing expected changes in bloodconcentration along the dialyzer fibers due to a change in thefiltration rate of a filter.

[0023]FIG. 4 is a single fiber fluid removal model.

[0024]FIG. 5 is a time tracing showing dialyzer blood flow recorded byan outflow sensor and showing coincident with a change in the filtrationrate a rise in blood concentration recorded by the outflow sensor.

[0025]FIG. 6 is a graph showing filter blood volume measurements byvolumetric measurement and dilution methods.

[0026]FIG. 7 is a chart of relative change of filter blood volume duringdialysis as measured by dilution and by reuse equipment.

[0027]FIG. 8 is a schematic view of a portion of the system showing anapparatus for monitoring a change in filter blood volume duringoperation of the filter.

[0028]FIG. 9 is a schematic view of a portion of the system showing anapparatus for monitoring filter blood volume during operation of thefilter.

[0029]FIG. 10 is a schematic view of a portion of the system showing analternative apparatus for monitoring filter blood volume in a filterduring operation of the filter.

[0030]FIG. 11 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter.

[0031]FIG. 12 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter.

[0032]FIG. 13 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter, the blood filter having a blood side anda dialysate side.

[0033]FIG. 14 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter, the blood filter having a blood side anda dialysate side having a known volume.

[0034]FIG. 15 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter, the blood filter having a blood side anda dialysate side.

[0035]FIG. 16 is a schematic view of a portion of the system showing afurther apparatus for monitoring filter blood volume in a blood filterduring operation of the filter, the blood filter having a blood side anda dialysate side.

[0036]FIG. 17 is a pair of graphs showing the relationship ofconcentration of the blood versus time during passage of a first bolusand a second bolus.

[0037]FIG. 18 is a system view of a filter incorporated in a circulationsystem having an apparauts for measuring filter blood volume and analarm system operably connected to the measuring apparatus.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] U.S. Pat. No. 5,453,576 (N. Krivitski) is hereby expresslyincorporated by reference.

[0039] The Apparatus

[0040]FIG. 1 discloses a schematic diagram having the main components ofa circulation system for passing blood through a filter. The apparatusfor calculating and monitoring a change in filter blood volume mayinclude a filter 20, a venous dilution sensor 40; a venous flow ratesensor 50; an injection port 60; an injectable indicator 70; an arterialdilution sensor 80; a pump 90; and an evaluating device 100. Asdiscussed, the invention may be practiced with an arterial flow ratesensor in place of or in addition to the venous flow rate sensor 50.Depending upon the particular configuration, the dilution sensor 40, 80may be used to also calculate the respective blood flow rate, therebyremoving the need for a separate flow rate sensor.

[0041] Referring to FIG. 1, “A” is designated as the arterial side and“V” is designated as the venous side. The term “upstream” is used todesignate a portion of the circulation system from which the fluid flowswith respect to a given position. Similarly, the term “downstream”designates a portion of the system to which fluid will flow from a givenposition.

[0042] The present system provides the real time calculating andmonitoring of volume of the filter 20. The relevant volume of the filter20 may be referred to as the filter blood volume (FBV) or the dialyzerblood volume (DBV) or fiber bundle volume, depending upon theconfiguration of the particular filter. The filter 20 may include asingle, or a plurality of tubes, plates, a conglomeration of biologicalcells or fibers across which a pressure differential is created. Eachconfiguration creates a volume in a filter 20, the FBV, which mayexperience a volume change in response to changes in bloodcharacteristics within the filter or due to the pressure change andfiltration rates. The term “blood side” of the filter 20 designates theportion of the filter through blood flows and the term “dialysate side”of the filter designates the portion of the filter through whichdialysate flows, wherein during operation of the filter selectivecomponents of the blood may pass from the blood side to the dialysateside or vise verse.

[0043] The filter 20 may be in the form of a dialyzer having an inlet22, a membrane through which a blood component may pass, and an outlet24. A particular dialyzer may be that sold by Baxter as CA-10, CF-25;Fresenius F80A, F80B; or Amicon Diafilter-30. It is understood thedialyzer may be a filter 20 of a dialysis type that employs a pressuredifferential, diffusion or osmosis to cause molecules of a given size topass through a membrane, or a filter that chemical or physicallyattaches to certain components in the blood.

[0044] The evaluating device 100 may be personal computer capable ofcurve plotting and performing the calculations set forth in the presentapplication. The evaluating device 100 receives signals from the sensorsand generates values representing flow rates and volumes and is capableof determining a mean transit time through the filter 20.

[0045] The present invention may include a feedback system forselectively triggering an alarm, upon a predetermined change in themeasured volume of the filter or heparin infusion or other anticogulantor other treatment substance.

[0046] Alternatively, the alarm may be triggered by a change in thevolume, independent of the measured volume.

[0047] The venous and arterial dilution sensors 40, 80 detect a bloodparameter or property, and particularly variations of the bloodparameter or property. Thus, the sensors 40, 80 are capable of sensing achange is a blood property, parameter or characteristic. For purposes ofthe disclosure the sensors 40, 80 may be referred to as dilutionsensors, but this label is not intended to limit the scope of availablesensors. Ultrasound velocity sensors as well as temperature sensors andoptical sensors, density or electrical impedance sensors, chemical orphysical sensors may be used to detect changes in blood parameters. Itis understood that other sensors that can detect blood property changesmay be employed. The operating parameters of the particular system willsubstantially dictate the specific design characteristics of thedilution sensor, such as the particular sound velocity sensor. Thevenous and arterial dilution sensors 40, 80 may be identical components.The venous and arterial dilution sensors 40, 80 are operably connectedto the evaluating device 100. The dilution sensors 40, 80 may be soundvelocity sensors and any of a variety of readily available commercialdevices, such as HD01 Hemodialysis monitor manufactured by TransonicSystems Inc. Ithaca N.Y.

[0048] The dilution sensors 40, 80 are selected to identify the passageof a bolus past the respective sensor. The term “bolus” is defined asany change in a blood property, parameter or characteristic, and mayinclude changes such as step functions and curvilinear dependencies. Thebolus may affect any of a variety of blood characteristics includingprotein concentration, electrical impedance, temperature, opticalproperties, sound velocity, hematocrit, chemical properties, andphysical properties including blood density.

[0049] A number of indicators 70 are capable of creating a bolus. Theindicator 70 is preferably injectable and may be any of the knownindicators including saline solution or any other solution that changesblood properties that can be detected by the dilution sensors. Theinjectable indicator 70 may be introduction of temperature gradient oranother blood property changes without introduction additional volume orother blood parameter, as well as a withdrawal of substances from blood.Preferably, the indicator is non toxic with respect to the patient ifused during a treatment procedure. The injected indicator 70 thus formsa bolus.

[0050] Depending upon the particular configuration of the system, asdescribed herein, the dilution sensor 40 is coupled to at least anvenous portion of a blood system for detecting the dilution of theblood, identifying a dilution curve. If the arterial dilution sensor 80is employed, it is operably connected to the arterial line and thevenous dilution sensor 40 is operably connected to the venous line.Ultrasonic sensors measure sound velocity dilution as the indicator iscarried past the sensor by the bloodstream, and changes in soundvelocity are plotted to permit calculation of various blood parameters.The time at which the indicator reaches the sensor after injection, thearea under the plotted curve representing the changes in sound velocityat the sensor, and the amplitude of the measurement all provideinformation concerning the blood characteristics.

[0051] The injection port 60 is located in the circulation system toallow selective access to the blood flow. The injection port 60 may beany of a variety of constructions allowing single or repeated access tothe blood flow. For example, the indicator 70 may be introduced intoarterial injection port 60 before the filter 20. Preferably, theindicator 70 is injectable through the injection port 60.

[0052] The flow sensors are used to measure the flow rate in the localsection of the circulation system. The flow rate sensors provide outputsignals corresponding to blood flow measurement. Each of the blood flowsensors may be a Bypass Flow Meter model HT 109 or model T106 producedby Transonic Systems, Inc., Ithaca, N.Y., for example. However, it isunderstood the dilution sensors may generate sufficient signals topermit measurement of the respective blood flow and thereby obviate thenecessity of a given flow sensor.

[0053] As an example of the dilution sensor 40 functioning, it isrecognized that the velocity of ultrasound in blood is a function of,among other things, the proteins and ions contained in the blood, withthe sound velocity increasing with an increase in protein concentration.Accordingly, the velocity of sound through a blood sample can be variedby diluting the blood with an indicator having different acousticalcharacteristics than those of the blood; for example, through the use ofa saline solution that has no proteins. By injecting such an indicator70 into a blood flow, the diluting effect of the indicator over a periodof time can be accurately determined by the sound velocity sensor whichis responsive to changes of sound velocity in the blood.

[0054] The dilution measurements can be made in an extracorporealportion of the circulation blood system in which clamp-on sound velocitysensors are secured for example, to tubing leading to exterior bloodtreatment equipment such as the hemodialysis machine, or the like asshown in FIG. 1. In such an embodiment, referred to as a clamp-onmeasurement system, measurements of blood are made outside the patient'sbody; for example, in extra corporeal tubing leading from the vascularsystem of the patient to a blood treatment system such as a dialysismachine. In such a system, blood is drawn from the patient, passedthrough suitable tubing to a dialysis filter and is then returnedthrough tubing to the patient, but downstream of the withdrawal site.Clamp-on sensors such as ultrasonic flow meters manufactured byTransonic Systems of Ithaca N.Y. are suitable for measuring blood flowthrough the tubing.

[0055] The Method

[0056] Generally, the present invention relates to methods and apparatusfor measuring or monitoring the volume of a blood side of a filter 20 byemploying one of a bolus in the blood side upstream of the filter;changing the filtration rate in the filter; and employing a bolus in thedialysate side.

[0057] The basis of the FBV calculations is generally based uponparticular indicator movement through the filter 20. The basis of thesecalculations are set forth.

[0058] Theoretical Analysis.

[0059] When flow in the system (Q) can be measured accurately, thevolume (V) of the system is determined by the following equation [5]:

V=Q×MTT  Eq. 1

[0060] where MTT (mean transit time) is the average time that theindicator travels through the system. Two methods, one based on a bolusinjection of normal saline and the other based on a step change infiltration rate of the filter, were employed for measuring the FBV. The“filtration rate” of the filter is the rate at which a particularmaterial passes from the blood side to the dialysate side. The stepchange in filtration rate may be accomplished by turning the filter onor off, or changing the rate at which matter crosses the filter.

[0061] Bolus Injection Method

[0062] Equation 1 assumes that the time required for injection of thebolus is negligible, that the bolus was introduced just before the inletto the dialyzer and that a dilution curve was recorded by the ultrasoundsensor immediately at the outlet to the filter. To eliminate theinfluence of the injection time and the distance between the site ofinjection and the filter entrance, an additional dilution sensor wasplaced on the blood inlet side of the filter as shown in FIG. 1. Toaccount for a finite injection time using the two sensors, Equation 1must be modified. For filtration through the filter turned off (a) andon (b):

FBV=Q _(b)×(MTT _(v) −MTT _(a))  Eq. 2a

FBV=(Q _(b)−0. 5Q _(f))×(MTT _(v) −MTT _(a))  Eq. 2b

[0063] where Qb is blood flow through the dialyzer; Qf is the filtrationflow rate; MTTv and MTTa are mean transit times of bolus (indicator)recorded by the sensors placed after the filter (venous line) and beforethe filter (arterial line) respectively. The formulas for calculatingMTT using this bolus injection method are [4]: $\begin{matrix}{{{MTT}_{a} = \frac{\int{{{Ca}(t)}y{t}}}{\int{{{Ca}(t)}t{t}}}}} & \text{Eq.~~3} \\{{MTT}_{v} = \frac{\int{{{Cv}(t)}{t}}}{\int{{{Cv}(t)}{t}}}} & \text{Eq.~~4}\end{matrix}$

[0064] where Ca(t) and Cv(t) are the concentration dilution curvesrecorded by the arterial and venous sensors, as shown in FIG. 2.

[0065] Filtration Method (Step Change)

[0066] The most convenient way to change blood properties (blooddensity, hemoglobin concentration, hematocrit, etc.) to allowmeasurement of volume, is to create a step change in the rate offiltration. When hydrostatic pressure is applied at the filter membrane,creating a gradient from the blood side to the dialysate side, the cellsand macromolecules in the blood are concentrated by continuous removalof filtrate from the entire filter blood compartment. This maneuver isanalogous to simultaneously adding indicator to the entire filter bloodcompartment. Referring to FIG. 3. when a steady state is reached, theblood at the entrance of the filter will be less concentrated than atthe exit where it is most concentrated. These conditions differ from thetraditional well developed methods for constant indicator infusionwhere, at steady state, the concentration in the system is the same inall locations.

[0067] The absence of an analytical formula for the relationship betweenoutflow concentration and FBV required development of a theoreticalmodel of changes in blood concentration at the dialyzer blood outlet inresponse to a step change in filtration. The analysis was performed intwo steps. First, the outflow concentration in a single fiber, as shownin FIG. 4, was evaluated after a step change in the filtration rate.Liquid flow balance and mass balance for non-removable blood particlesin the fiber were used to develop the differential equations. Second,the results obtained for one fiber were expanded to the whole dialyzerwith the assumption that the fractional removal of filtrate from theblood compartment is the same for all fibers that take part infiltration.

[0068] Specifically, it was assumed that fractional removal of fluid (F)was uniform throughout the volume of blood in the filter and in thefibers.

F=Qf/FBV[ml/sec/ml=1/sec]  Eq. a1

[0069] Single Fiber Analysis

[0070] Single fiber concentration changes are schematically shown inFIG. 4. After filtration is turned on, the change in concentrationwithin a single fiber is calculated based on liquid flow balance and nonremovable particles balance.

[0071] Liquid flow balance provides:

v(x)×S=v(x+Δx)×S+F×Δx×S  Eq. a2

[0072] where v(x) is the average linear velocity of liquid at point x; Sis the cross sectional area of the fiber; F is the fractional rate offiltration in the fiber, from Equation a1.

[0073] The second of the two terms summed in Equation a2 represents theflow of filtrate removed from the fiber as the blood flows along thedistance Δx.

[0074] Equation a2 may be rewritten in differential form:

v′(x)=−F  Eq. a3

[0075] The solution of this equation is:

v(x)=v*−F×x  Eq. a4

[0076] where v* is the average linear velocity of blood at the entranceto the fiber.

[0077] From a consideration of mass balance for non removable bloodparticles:

C(x,t)×v(x)=C(x+Δx,t+Δt)×v(x+Δx)  Eq. a5

[0078] where C(x,t) is the concentration of non removable bloodparticles (red blood cells, hemoglobin's etc.)

[0079] The relationship between Δx and Δt, as Δx and Δt→0, may beexpressed, as: $\begin{matrix}{\frac{\Delta \quad x}{\Delta \quad t} = {v(x)}} & \text{Eq.~~a6}\end{matrix}$

[0080] This means that the movement of particle packet is beingrecording. Decomposing the right part of Equation a5 in a Taylor seriesgives:

v(x+Δx)=v(x)+v′(x)×Δx  Eq. a7

[0081] $\begin{matrix}{{C\left( {{x + {\Delta \quad x}},{t + {\Delta \quad t}}} \right)} = {{C\left( {x,t} \right)} + {\frac{\partial{C\left( {x,t} \right)}}{\partial x} \times \Delta \quad x} + {\frac{\partial{C\left( {x,t} \right)}}{\partial t} \times \Delta \quad t}}} & \text{Eq.~~a8}\end{matrix}$

[0082] Combining Equations a5-a8 with consideration of Equation a3 andneglecting small values of the second order gives: $\begin{matrix}{{{C\left( {x,t} \right)} \times F} = {{C\left( {x,t} \right)} + {\frac{\partial{C\left( {x,t} \right)}}{\partial x} \times {v(x)}} + \frac{\partial{C\left( {x,t} \right)}}{\partial t}}} & \text{Eq.~~a9}\end{matrix}$

[0083] Before filtration is turned on, the concentration ofnondiffusable particles was the same along the entire fiber (Equationa10) and was equal to the entering (initial) concentration Co that wasconsidered constant during the measurement (Equation a11):

C(x,0)=Co L≧x≧0  Eq. a10

C(0,t)=Co  Eq. a11

[0084] Because the concentration sensor is located at the exit of thefilter the particular interest was in the outflow concentration at x=L,as shown in FIG. 3. The solution of Equation a9 consists of 2 parts. Thefirst part is related to the concentration of blood that was in thefiber at the moment when filtration was turned on. The second part isrelated to the blood that enters the filter after filtration was turnedon and reaches location x=L at time t* after passing through the entirefiber. After this moment, the process in this fiber achieves a steadystate. The first part of the solution for t<t*:

C(L,t)=C(L,0)×exp(F×t)=Co×exp(F×t)  Eq. a12

[0085] The second part of the solution for t>t* for x=L: $\begin{matrix}{{C\left( {L,t} \right)} = {{Co} \times \frac{1}{1 - {F \times \frac{L}{v^{*}}}}}} & \text{Eq.~~a13}\end{matrix}$

[0086] Equation a12 gives the concentration changes during the transferprocess and depends only on time “t” and F. It is also clear fromEquation a12 that the concentration will be the same for any fiber inthe dialyzer at moment “t”. Equation a13 gives the concentration duringthe steady state and does not depend on time. The outflow concentrationof every fiber will depend on v*, the average linear velocity of liquidat the fiber entrance that may be different for every fiber due todifferent inner diameters. So in contrast to Equation a12 the outflowconcentration at t>t* may be different for every fiber.

[0087] In the second step, the analysis is applied to the entire filterconcentration changes. The resulting concentration in the filteroutflow, Cv(L,t), is the sum of outflow concentrations in all fibersmultiplied on their flow and divided by total flow: $\begin{matrix}{{{Cv}\left( {L,t} \right)} = \frac{\sum{{C_{n}\left( {l,t} \right)} \times S_{n} \times v^{*}}}{\sum{S_{n} \times v_{n}^{*\quad}}}} & \text{Eq.~~a14}\end{matrix}$

[0088] where n=1 . . . n; n is the number of fibers in dialyzer; Cn(L,t)is the outflow concentration of the “nth” fiber; Sn is the crosssectional area of the “nth” fiber;

[0089] V*_(n) is an average line blood flow in the “nth” fiber.

[0090] It is clear from Equation a12 that the outflow concentration inEquation a14 in every fiber at time “t” is the same until the momentwhen, in one of the fibers, t>t*:

C _(n)(L,t)=Co×exp(F×t)  Eq. a15

[0091] For dialyzer outflow:

ΣS_(n) ×v* _(n) =Q _(b)−Q_(f)  Eq. a16

[0092] Considering Equations a12, a15 and a16, Equation a14 may besimplified for any t<t*:

C _(v)(L,t)=Co×exp(F×t)  Eq. a17

[0093] Equation a17 for the entire filter is the same as for one fiber.This condition exists until, in any single fiber, the blood that entersthe fiber after filtration was turned on reaches x=L (i.e., it passesthrough the entire length of the fiber). Estimating the practical valueof exponent F×t, for Qf in the range 10-20 ml/min, dialyzer blood volume60-120 ml, the estimation of F gives F=0.0014-0.0056/sec. For time t inthe order of 7-10 sec, the value of F×t will be in the order of0.01-0.05<<1. Then with accuracy of less than 1% error, Equation a17 maybe rewritten: $\begin{matrix}{{C_{v}\left( {L,t} \right)} = {{{Co} \times \left( {1 + {F \times t}} \right)} = {{Co} \times \left( {1 + \frac{Q_{f} \times t}{FBV}} \right)}}} & \text{Eq.~~a18}\end{matrix}$

[0094] and the dialyzer blood volume after filtration is turned on canbe calculated from Equation a18: $\begin{matrix}{{{FBV} = \frac{{Co} \times Q_{f} \times t}{\left( {{C_{v}\left( {L,t} \right)} - {Co}} \right)}}{or}} & \text{Eq.~~a19} \\{{FBV} = {{Co} \times \frac{Q_{f}}{\tan \quad \alpha}}} & \text{Eq.~~a20}\end{matrix}$

[0095] where tan α is calculated from FIG. 5.

[0096] Equation a20 can also be represented in a different form to avoidmeasurement of the absolute concentration Co. The mass balance of largeparticles that do not diffuse through the filter at steady state may beexpressed as:

Q _(b) ×Ca*=(Q _(b)−Q_(f))×Cv*  Eq. a21

[0097] where Ca* and Cv* are concentrations of large particles in thefilter arterial and venous blood at steady state, respectively.

[0098] Before filtration is turned on or changed, the initialconcentration in the venous line is the same as in the arterial line(Co=Ca). The initial venous concentration, Co, will be the same as Ca*at steady state if Ca does not change during transfer time Ttr. A changein Ca may occur if the concentration change introduced by a change infiltration recirculates through the dialyzer (FBV), through the arterialand venous tubing (Vav), and then through the cardiopulmonary system(Tcp) before a steady state is reached. Ttr can be estimated based onexisting tubing systems and dialyzers: $\begin{matrix}{{Tr} \cong \frac{\left( {V_{av} + {FBV}} \right)}{Q_{b} + T_{cp}}} & \text{Eq.~~a22}\end{matrix}$

[0099] The quickest return (worst case scenario) in the absence ofaccess recirculation: Vav=100 ml; FBV=60 ml; Qb=500 ml/min; Tcp=10 sec,gives Ttr=30 sec. This time is sufficiently long to allow a steady stateto be reached across the dialyzer.

[0100] For these conditions, Equation a21 may be rewritten (Ca*=Ca=Co):$\begin{matrix}{{{Cv}^{*} - {Co}} = {{Cv} \times \frac{Q_{f}}{Q_{b}}}} & \text{Eq.~~a23}\end{matrix}$

[0101] Finally, from Equation a20, substituting${\tan \quad \alpha} = \frac{\left( {{Cv}^{*} - {Co}} \right)}{T}$

[0102] (as shown in FIG. 5, and considering Equation a23, the formulafor FBV when filtration is turned on is:

FBV=(Q _(b) −Q _(f))×T  Eq. a24

[0103] When these measurements were performed by turning filtration offinstead of turning it on, the initial steady state concentration alongthe dialyzer will be similar to that shown in FIG. 3. The equation forconcentration in a single fiber before filtration is turned off is (seeEquation 13a): $\begin{matrix}{{C\left( {x,{t = 0}} \right)} = {{Co} \times \frac{1}{1 - {F \times \frac{x}{v^{*}}}}}} & \text{Eq.~~a25}\end{matrix}$

[0104] where t=0 signifies the time at the beginning of the process, andv* is the same at any place in the fiber. The fiber outflowconcentration at time “t” depends on how far this portion is located(distance L−x) from the exit. The amount of time “t” required for theportion of the blood located at coordinate “x” to reach the fiber exitis: $\begin{matrix}{t = \frac{\left( {L - x} \right)}{v^{*}}} & \text{Eq.~~a26}\end{matrix}$

[0105] The outflow concentration from Equation a25 and Equation a26 is:$\begin{matrix}{{C\left( {L,t} \right)} = {{Co} \times \frac{1}{\left\lbrack {1 - \frac{F \times \left( {L - {v^{*} \times t}} \right)}{v^{*}}} \right\rbrack}}} & \text{Eq.~~a27}\end{matrix}$

[0106] A practical estimation of F×t<<1 was described above; the sameconditions may be applied to the expression in squared brackets ofEquation a27: $\begin{matrix}{{{C\left( {L,t} \right)} = {{Co} \times \left\lbrack {1 + {F \times \frac{\left( {L - {v^{*} \times t}} \right)}{v^{*}}}} \right\rbrack}}{or}} & \text{Eq.~~a28} \\{{C\left( {L,t} \right)} = {{{Co} \times \left\lbrack {1 + {F \times \frac{L}{v^{*}}}} \right\rbrack} - {{Co} \times F \times t}}} & \text{Eq.~~a29}\end{matrix}$

[0107] The first part of the sum is the outflow concentration in thefiber at steady state before filtration is turned off (or changed). Theresulting filter outflow concentration Cv(L,t) is the sum of outflowconcentrations in all fibers (Equation a29) multiplied by theirindividual flows and divided by the total flow (Equation a14). The firstpart of the sum gives the initial level Cv*:

Cv(L,t)=Cv**−Co×F×t  Eq. a30

[0108] or from Equation a1: $\begin{matrix}{{FBV} = \frac{{Co} \times Q_{f} \times t}{\left( {{Cv}^{**} - {{Cv}\left( {L,t} \right)}} \right)}} & \text{Eq.~~a31}\end{matrix}$

[0109] or by analogy with Equation a20: $\begin{matrix}{{FBV} = {{Co}^{*} \times \frac{Q_{f}}{\tan \quad \alpha}}} & \text{Eq.~~a32}\end{matrix}$

[0110] and also by analogy with Equation a24:

FBV=(Q _(b) −Q _(f))×T  Eq. a33

[0111] The resulting formulas for FBV (Equations a20 and a32; Equationsa24 and a33) are the same regardless of whether FBV is measured byturning filtration on or by turning it off, or changing the filtrationrate.

[0112] The fractional removal rate is Qf/FBV. Two modifications of thisformula (Equations a20 and a24) were derived for FBV when filtrationoccurs during dialysis (filtration turned on): $\begin{matrix}{{FBV} = {{Co} \times \frac{Q_{f}}{\tan \quad \alpha}}} & \text{Eq.~~5}\end{matrix}$

[0113] or:

FBV=(Q _(b) −Q _(f))×T  Eq. 6

[0114] where Co is the initial concentration, before filtration isturned on as shown in FIG. 5, of non-diffusable substances recorded bythe venous sensor; tan and T are calculated from the subsequent changesin concentration. For the case when filtration is turned off see theanalogous formulas (Equations a32 and a33).

[0115] A change in the FBV may be measured from monitoring a change inthe filtration rate, without requiring a measurement of the flow ratethrough the blood side or the dialysate side. In particular, a firstblood parameter measurement is obtained downstream of a blood side ofthe filter after a first filtration rate change (T1). A second bloodparameter measurement is then obtained downstream of a blood side of thefilter after a second filtration rate change (T2). Any change in the FBVis calculated from the first blood parameter measurement and the secondblood parameter measurement. Specifically, the change in FBV may bedetermined by$\frac{\Delta \quad V_{B}}{V_{B}} = {\frac{T_{2} - T_{1}}{T_{1}}.}$

[0116] Referring to FIG. 5, the change in FBV may also be calculated as${\frac{\Delta \quad V_{B}}{V_{B}} = \frac{\left( {{\tan \quad {\alpha 2}} - {\tan \quad {\alpha 1}}} \right)}{\tan \quad {\alpha 1}}};$

[0117] wherein tan α1 is the tangent of the graphic angle formed by thefirst filtration rate change and tan α2 is the tangent of the graphicangle formed by the second filtration rate change.

[0118] Accuracy and Reproducibility

[0119] The reproducibility of both the bolus and the filtration methodsaveraged 1% to 4% for both in vitro and in vivo FBV measurements. Thebolus method (FIG. 6) showed substantial agreement with volumetricgraduated cylinder method measurements (mean error 0.16±4.23%, n=42)while filtration method significantly underestimated FBV when measuredvolumetrically by the (15% lower, p<0.01).

[0120] As the filtration method measures the volume that is directlyinvolved in the filtration process, the results were consistent withexpectations. The blood volume in the portion of the fibers imbedded inpotting material at both ends of the filter (FIG. 3) as well as theblood volume taken up by the headers does not take part in the exchangeprocess and therefore would not be a part of the filtrationmeasurements. In contrast, this volume is taken into account by thebolus method, by the graduated cylinder method, and by the reuse machinemeasurements. When a simple geometrical calculation was used to estimatethis “inactive” volume the differences between the filtration method andthe graduated cylinder method were minor, 2.10±7.26%.

[0121] When compared with volumetric measurements (graduated cylinder)and with measurements by the bolus dilution method, FBV measured by thereuse machine was respectively 4% and 5% less. This small discrepancymay be due to an inability of the reuse machine to completely flushsaline from the fibers.

[0122] Both the bolus injection and the filtration technologies can bemodified for routine clinical measurements of FBV. Sensors may be movedcloser to the patient to the optimal position for measuring access flowand access recirculation. For the bolus method the injections into thearterial line can be replaced by a bolus released from the saline baglike a recently described method for access flow measurements. Thefiltration step change method provides further benefits. The filtrationstep change method requires only one (post-filter) sensor, it is simplerto perform and to automate and it appears, based on the abovediscussion, that the volume measured is more pertinent to the clinicalconsequence of fiber clotting causing a reduction in solute clearance.

[0123] Clinical Relevance

[0124] The data shown in FIG. 7 suggests that a significant decrease inFBV during dialysis treatments may not be detected by the reuse machine.One must also suspect that in the 6 of 31 treatments where FBV droppedmore then 10%, the delivered dose of dialysis was reduced. Thediscrepancy between FBV measured during dialysis by ultrasound dilutionand following dialysis by the reuse machine may be explainable.Specifically, the fibrous threads that result from clotting within thehollow fibers during dialysis are often seen during pressure rinsing ofthe dialyzer after the session. The observed difference between real FBVduring dialysis and assumed FBV measured by the reuse machine may alsopartly explain results observed by different investigators who examinedthe effect of dialyzer reuse on performance of the dialyzer.

[0125] Possible applications in hemodialysis and hemofiltration for thison-line technology, including treatment for acute renal failure include:

[0126] 1. Early warning of ongoing clotting for conventional and heparinfree dialysis;

[0127] 2. Quality control of dialyzer reuse;

[0128] 3. Solute clearance control;

[0129] 4. Use of machines to measure FBV without requiring the use ofblood, such as in reuse machines;

[0130] 5. Use in filters where biological cells are the filter media;and

[0131] 6. Optimization of heparin administration.

[0132] The theoretical analysis, bench validations, and preliminaryclinical data suggest that FBV can be accurately and simply measured byindicator dilution techniques in vivo during hemodialysis and that FBVmeasured by reuse equipment may not always represent the real dialyzerblood volume during hemodialysis.

[0133] Further, it is understood the measurement of FBV may be made whenthe filter is not actively connected to a patient, or activelyfiltering. That is, the present invention provides for the testing offilters prior to use, merely upon operatively connecting a filter to therequisite sensors. That is, the present invention may be used in placetraditional flushing and volumetric methods.

[0134] For purposes of description, it is understood in the followingconfigurations, that the components are operably connected. For example,the sensor 40 is connected to the evaluating device 100, and the sensoris operably connected to the fluid path of the blood flow.

[0135] Referring to FIG. 8, a configuration for monitoring a change in avolume of blood in a filter 20 during operation of the filter is shown.This configuration includes a dilution sensor 40 in the blood sidedownstream of the filter 20 and the injection port 60 on the blood sidelocated upstream of the filter. In this system, the method determines achange in the filter blood volume by the relationship:$\frac{\Delta \quad V_{B}}{V_{B}} = \frac{{Q_{B}\left( {MTT}_{2} \right)} - {Q_{B}\left( {MTT}_{1} \right)}}{Q_{B}\left( {MTT}_{1} \right)}$

[0136] where V_(B) is the blood filter volume; Q_(B) is the flow ratethrough the blood filter and MTT is the mean transit time of therespective bolus. For flow rate through the filter being constant, thechange in FBV becomes:$\frac{\Delta \quad V_{B}}{V_{B}} = \frac{{MTT}_{2} - {MTT}_{1}}{{MTT}_{1}}$

[0137] In operation, a first bolus is injected through the injectionport 60 and a first downstream signal is generated as the first boluspasses the dilution sensor downstream of the filter 20. Preferably, thefirst downstream signal is the mean transit time MTT1 for passage of thefirst bolus past the dilution sensor 40. A second bolus is then injectedthorough the injection port 60 and a second downstream signal isgenerated as the second bolus passes the dilution sensor 40 downstreamof the filter. Preferably, the second downstream signal is the meantransit time MTT1 for passage of the second bolus past the dilutionsensor 40.

[0138] Thus, a change in FBV during operation of the filter 20 can bedetermined by introducing a first bolus upstream of the filter duringoperation of the filter; obtaining a signal downstream the filtercorresponding to the passage of the first bolus through the filter andpast the sensor 40; introducing a second bolus upstream of the filterduring operation of the filter; obtaining a signal downstream the filtercorresponding to the passage of the second bolus through the filter andpast the sensor; and calculating the change in FBV from the signalobtained from the first and second bolus introduction.

[0139] It is understood the accuracy may be enhanced by determining ablood flow rate through the filter 20 and particularly a blood flow rateupstream and downstream of the filter. Thus, a change in the FBV can bedetermined in real time.

[0140] Referring to FIG. 9, a configuration for monitoring a volume ofblood in a blood filter 20 during operation of the filter is shown. Thisconfiguration includes a dilution sensor 40 on the blood side downstreamof the filter and the injection port 60 on the blood side locatedupstream of the filter. In addition, the system includes a sensor 50 formeasuring the blood side flow rate. Preferably, the sensor 50 is a flowrate sensor and is located downstream of the filter. It is alsounderstood the flow rate may measured via the dilution sensor 40,thereby obviating the need for a separate flow rate sensor. In thissystem, the method determines FBV by the relationship:

[0141] V_(B)=Q_(B) (MTTv) where MTTv is the mean transit time of thebolus past the downstream (venous) dilution sensor and Q_(B) is the flowrate through the blood filter.

[0142] In operation, a bolus is injected through the injection port 60upstream of the filter 20. In a preferred condition, the bolus isintroduced sufficiently near the filter 20 to substantially precludecompensation of a downstream signal. The flow rate is determined by theflow rate sensor 50, or via the dilution sensor 40, where the flow rateis calculated from the same dilution signal from the sensor 40. A signalcorresponding to passage of the bolus past the dilution sensor 40 isobtained. Preferably, the signal is the mean transit time for passage ofthe bolus past the dilution sensor.

[0143] Thus, the FBV may be calculated by introducing a bolus upstreamof the filter 20 during operation of the filter and sufficiently nearthe filter to substantially preclude compensation of a downstreamsignal; obtaining the downstream signal corresponding to passage of thebolus downstream of the filter; measuring a blood flow rate through thefilter; and calculating the blood volume of the filter in response tothe downstream signal and the measured blood flow rate.

[0144] Referring to FIG. 10, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a blood side dilution sensor 40 downstream of thefilter and an injection port 60 located on the blood side upstream ofthe filter. The injection port 60 is located sufficiently far upstreamof the filter 20 that an accommodation or correction must be made forthe volume of the tubing between the injection port and the filter. Inaddition, the system includes a sensor 50 for measuring the blood sideflow rate. Preferably, the sensor 50 is a flow rate sensor is locateddownstream of the filter. It is also understood the flow rate maymeasured via the dilution sensor 40, thereby obviating the need for aseparate flow rate sensor. In this system, the method determines FBV bythe relationship:$V_{B} = {Q_{B}\left( {{MTTv} - \frac{V_{art}}{Q_{B}}} \right)}$

[0145] where MTTv is the mean transit time of the bolus past thedownstream (venous) dilution sensor and V_(art) is the volume of thearterial section intermediate the injection port and the filter.

[0146] Thus, the FBV may be measured during operation of the filter 20by introducing a bolus upstream of the filter during operation of thefilter at a given time. A volume of blood intermediate the injectionport 60 and the filter 20 is either determined, calculated or know(based upon tubing geometry). A signal is obtained downstream of thefilter corresponding to the passage of the bolus. The signal may be themean transit time. The blood flow rate through the filter 20 is measuredby a flow rate sensor 50 or calculated from the dilution sensor 40. TheFBV is then calculated based upon the given time, the signal obtaineddownstream the filter, the measured blood flow rate and the identifiedvolume of blood between the place of in indicator introduction and thefilter.

[0147] Referring to FIG. 11, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a blood side dilution sensor 80 upstream of thefilter 20, a blood side dilution sensor 40 downstream of the filter andthe injection port 60 located on the blood side and upstream of thefilter. In addition, the system includes a sensor 50 for measuring theblood side flow rate. Preferably, the sensor 50 is a flow rate sensor islocated downstream of the filter. It is also understood the flow ratemay measured via the dilution sensor 40 or sensor 80, thereby obviatingthe need for a separate flow rate sensor. In this system, the methoddetermines FBV by the relationship:

V _(B) =Q _(B)(MTTv−MTT _(A))

[0148] where MTT_(A) is the mean transit time of the bolus past theupstream (arterial) dilution sensor; MTTv is the mean transit time ofthe bolus past the downstream (venous) dilution sensor and Q_(B) is theflow rate through the blood filter.

[0149] Thus, the configuration provides for measuring the FBV duringoperation of the filter 20 by first introducing a bolus upstream of thefilter. An upstream signal is obtained corresponding to passage of thebolus past the upstream dilution sensor 80. A downstream signal isobtained corresponding to passage of the bolus past the downstreamdilution sensor 40. The blood flow rate through the filter 20 is thenmeasured, calculated or determined. Finally, the FBV is calculated inresponse to the upstream and downstream signals and the measured bloodflow rate. It is understood the upstream signal and the downstreamsignal may correspond to the respective mean transit times. Further, theblood flow rate may be calculated from one of the upstream and thedownstream dilution signals.

[0150] Referring to FIG. 12, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a dilution sensor 40 on the blood side downstreamof the filter. In addition, the system includes a sensor 50 formeasuring the blood side flow rate. Preferably, the sensor 50 is a flowrate sensor is located downstream of the filter. It is also understoodthe flow rate may measured via the dilution sensor 40, thereby obviatingthe need for a separate flow rate sensor. In this system, the methoddetermines FBV by the relationship described in the previous section ofthe disclosure. This method employs a manipulation of the filtrationrate and the corresponding time for the change in the blood property.Thus, the FBV may be monitored during operation of the filter 20 bymeasuring a blood parameter downstream of the blood side of the filter.The blood flow rate through the blood side of the filter 20 is thenmeasured, calculated or determined. The filtration rate is then changedto cause a change in the measured blood parameter. The FBV is thencalculated corresponding to the measured change of the blood parameterand the blood flow rate.

[0151] Referring to FIG. 13, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a blood side dilution sensor 40 downstream of thefilter. In addition, the system includes a sensor 110 for measuring thedialysate flow rate. Preferably, the sensor 110 is a flow rate sensorand is located on the dialysate side of the filter 20 and downstream ofthe filter. In this system, the method determines FBV by therelationship described in the previous section of the disclosure.

[0152] Thus, the FBV may be monitored during operation of the filter 20by measuring a blood parameter in the blood side downstream of thefilter. The flow rate through the dialysate side of the filter ismeasured. The filtration rate of the filter 20 is changed to change themeasured blood parameter. The FBV may then be calculated from thechanged blood parameter and the measured flow rate through the dialysateside.

[0153] Referring to FIG. 14, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a dilution sensor 140 on the dialysate side ofthe filter, downstream of the filter. In addition, the system includes asensor 110 for measuring the dialysate flow rate. Preferably, the sensor110 is a flow rate sensor is located on the dialysate side of the filter20 and upstream of the filter. An injection port 62 is provided on thedialysate side of the filter 20. In this system, the method determinesFBV by the relationship:

V _(B) =Q _(D)(MTT _(diff) −V _(dialyzer))

[0154] where Q_(D) is the flow rate through the dialysate side of thefilter; MTT_(diff) is the mean transit time for a diffusable bolus andV_(dialyzer) is the volume of the dialysate side of the filter 20. Thevolume of the dialysate side of the filter 20 is generally known or maybe readily calculated by traditional methods.

[0155] Thus, a volume of blood in a blood filter 20 may be measuredduring operation of the filter by changing a parameter of dialysate inthe dialysate side of the filter upstream of the filter. Preferably, adiffusable bolus is passed through the filter 20 to change the bloodparameter. A change in the dialysate downstream of the filter due topassing the diffusable bolus through the filter is measured. The bloodflow rate in the dialysate side of the filter 20 is measured. Finally,FBV is calculated in response to the measured changes in dialysateparameter, the flow rate and the known volume of the dialysate side.

[0156] Referring to FIG. 15, a configuration for monitoring a volume ofblood in a filter 20 during operation of the filter is shown. Thisconfiguration includes a dilution sensor 140 on the dialysate side ofthe filter, downstream of the filter. At least one injection port 62 andpreferably two injection ports are located on the dialysate side of thefilter 20. This configuration employs a first diffusable bolus and asecond non diffusable bolus passing through the dialysate side of thefilter 20. In this system, the method determines FBV by the relationshipas set forth for FIG. 14 as well as that a second bolus is introduced:

V _(dialyzer) =Q _(D)(MTT _(nondiff))

[0157] where Q_(D) is the flow rate through the dialysate side of thefilter; MTT_(nondiff) is the mean transit time for the non diffusablebolus and V_(dialyzer) is the volume of the dialysate side of the filtermeasured by dilution with the non diffusable bolus.

[0158] Hence, the blood volume of the filter 20 may be represented as

FBV=Q _(D)(MTT _(diff) −MTT _(nondiff))

[0159] where Q_(D) is the flow rate through the dialysate side of thefilter; MTT_(nondiff) is the mean transit time for the non diffusablebolus and MTT_(diff) is the mean transit time for the diffusable bolus.

[0160] Thus, the FBV may be measured during operation of the filter 20by injecting a non diffusable bolus upstream of the dialysate side ofthe filter. An injection or introduction of a diffusable bolus upstreamof the dialysate side of the filter 20 is also made. A dilution curvecorresponding to passage of the non diffusable bolus downstream of thefilter 20 is measured. A dilution curve corresponding to passage of thediffusable bolus downstream of the filter 20 is also measured. The flowrate through the dialysate side of the filter is measured. Finally, theFBV is calculated in response to the dilution curve from diffusablebolus and nondiffusable bolus and the measured flow rate through thedialysate side.

[0161] Referring to FIG. 16, a configuration for monitoring a volume ofblood in a filter during operation of the filter is shown. Thisconfiguration includes a first dilution sensor 140 and a second dilutionsensor 140 on the dialysate side of the filter 20, downstream of thefilter. This configuration employs a first diffusable bolus and a secondnon diffusable bolus passing through the dialysate side of the filter20, wherein the first bolus and the second bolus are substantiallysimultaneously introduced.

[0162] Thus, a volume of blood in a blood filter 20 may be measuredduring operation of the filter by injecting a bolus of a diffusableindicator and a non diffusable indicator upstream of the filter on thedialysate side of the filter. A dilution curve corresponding to passageof the diffusable indicator downstream of the filter on dialysate sideis measured by the first dilution sensor 140. A dilution curvecorresponding to passage of the non diffusable indicator downstream ofthe filter on dialysate side is measured by the second dilution sensor140. The flow rate through the dialysate side is measured. Finally, aFBV is calculated from dilution curves of the diffusable indicator andthe nondiffusable indicator and the measured flow rate through thedialysate side of the filter.

[0163] As previously stated, the present invention may include afeedback system for selectively triggering an alarm, upon apredetermined change in the measured volume of the filter, or a heparininfusion or other anticoagulant or other treatment substance.Alternatively, the alarm may be triggered by a change in the volume,independent of the measured volume. The feedback may be configured as aloop or a single direction signal which prompts operator response.

[0164] Referring to FIG. 18, each of the configurations of the presentinvention may be employed in cooperation with an alarm (alert) system150 and/or a blood characteristic modifier 160 such as an infusionsystem.

[0165] The alarm system 150 is operably connected to the evaluatingdevice 100 and may provide an alarm in response to a signal from theevaluating device. The alarm signal may be set to respond to apredetermined change in FBV volume, an absolute FBV or a combination ofboth. The alarm may be in the form of an audible alarm or a visualalarm. In addition, it is contemplated the alarm system 150 is operablyconnected to the blood characteristic modifier 160. Thus, in additionto, or in place of the alarm, the blood characteristic modifier 160 mayautomatically alter a parameter of the system by changing filtrationrates, discontinuing a process or adding material to the blood flow,such as through an infusion device.

[0166] The blood characteristic modifier 160 may be operably located atany point in the circulation system as dictated by the intendedoperation and type of modification. For example, the bloodcharacteristic modifier 160 may be connected to the blood flow path, thefilter 20 or a fluid system in conjunction with the filter. The presentinvention thereby provides a method and apparatus for monitoring the FBV(or change in FBV) and a feedback and control system for responding,either selectively or automatically, to the monitored FBV.

[0167] While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiments,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims which scope is to be accorded the broadestinterpretation so as to encompass all such modifications and equivalentstructures.

1. A method for monitoring a change in a volume of blood in a filterduring operation of the filter, comprising: (a) introducing a firstbolus upstream of the filter during operation of the filter; (b)obtaining a first signal downstream of the filter corresponding to thepassage of the first bolus through the filter; (c) introducing a secondbolus upstream of the filter during operation of the filter; (d)obtaining a second signal downstream of the filter corresponding to thepassage of the second bolus through the filter; (e) calculating thechanges in blood volume of the filter from the first signal and thesecond signal.
 2. The method of claim 1, further comprising measuring ablood flow rate through the filter.
 3. The method of claim 1, furthercomprising obtaining a third signal upstream of the filter correspondingto the passage of the first bolus upstream of the filter; obtaining afourth signal upstream of the filter corresponding to the passage of thesecond bolus upstream of the filter and calculating the change in bloodvolume in response to the first signal, the second signal, the thirdsignal and the fourth signal.
 4. The method of claim 1, furthercomprising employing a mean transit time for the first bolus and secondbolus.
 5. A medical device for processing a quantity of blood in a fluidpath, comprising: (a) a filter having a filter blood volume; (b) aninjection port in the fluid path upstream of the filter for introducinga bolus into the fluid path; (c) a blood parameter sensor downstream ofthe filter for generating a signal corresponding to passage of the boluspast the sensor; and (d) means for calculating a change in the filterblood volume in response to the generated signal.
 6. The medical deviceof claim 5, wherein the blood parameter sensor is a dilution sensor. 7.A method for monitoring a volume of blood in a blood filter duringoperation of the filter, comprising: (a) introducing a bolus upstream ofthe filter during operation of the filter and sufficiently near thefilter to substantially preclude compensation of a downstream signal;(b) obtaining the downstream signal corresponding to passage of thebolus downstream of the filter; (c) measuring a blood flow rate throughthe filter; and (d) calculating the blood volume of the filter inresponse to the downstream signal and the measured blood flow rate. 8.The method of claim 7, further comprising measuring the blood flow ratein response to the downstream signal.
 9. The method of claim 7, furthercomprising measuring the blood flow rate with a blood flow sensor.
 10. Amedical device for processing a quantity of blood in a fluid path,comprising: (a) a filter having a filter blood volume; (b) an injectionport in the fluid path upstream of the filter for introducing a bolusinto the fluid path, the injection port being sufficiently near thefilter to substantially preclude compensation of a downstream signal;(c) a blood parameter sensor downstream of the filter for generating thedownstream signal corresponding to passage of the bolus past the sensor;(d) means for determining a flow rate in the fluid path; and (e) meansfor calculating the filter blood volume in response to the downstreamsignal and the flow rate.
 11. The medical device of claim 10, whereinthe means for determining a flow rate in the fluid path includes a flowrate sensor.
 12. The medical device of claim 10, wherein the means fordetermining a flow rate in the fluid path determines the flow rate inresponse to the generated downstream signal.
 13. A method for monitoringa volume of blood in a filter during operation of the filter,comprising: (a) introducing a bolus upstream of the filter duringoperation of the filter at a given time; (b) identifying a volume ofblood between the bolus introduction and the filter; (d) obtaining asignal downstream the filter corresponding to the passage of the bolusthrough the filter; (e) measuring a blood flow rate through the filter;and (f) calculating the blood volume of the filter from the given time,the signal obtained downstream the filter, the measured blood flow rateand the identified volume of blood between the place of in indicatorintroduction and the filter.
 14. The method of claim 13, furthercomprising calculating the blood flow rate from the signal downstream ofthe filter.
 15. The method of claim 13 further comprising measuring,calculating or knowing the volume of blood between the bolusintroduction and the filter.
 16. A medical device for processing aquantity of blood in a fluid path, comprising: (a) a filter having afilter blood volume; (b) an injection port in the fluid path upstream ofthe filter for introducing a bolus into the fluid path, the injectionport spaced from the filter to define an arterial volume in the fluidpath between the injection port and the filter; (c) a blood parametersensor downstream of the filter for generating a downstream signalcorresponding to passage of the bolus past the sensor; (d) means fordetermining a flow rate in the fluid path; and (e) means for calculatingthe filter blood volume in response to the downstream signal, thearterial volume and the flow rate.
 17. The medical device of claim 16,wherein the means for determining a flow rate in the fluid path includesa flow rate sensor.
 18. The medical device of claim 16, wherein themeans for determining a flow rate in the fluid path determines the flowrate in response to the downstream signal.
 19. A method for monitoring avolume of blood in a blood filter during operation of the filter,comprising: (a) introducing a bolus upstream of the filter duringoperation of the filter; (b) obtaining an upstream signal correspondingto passage of the bolus past a point upstream of the filter; (c)obtaining a downstream signal corresponding to passage of the bolus pasta point downstream of the filter; (d) measuring a blood flow ratethrough the filter; and (e) calculating the blood volume of the filterin response to the upstream and downstream signals and the measuredblood flow rate.
 20. The method of claim 19, further comprisingcorresponding the upstream signal and the downstream signal to a meantransit time of the bolus.
 21. The method of claim 19, furthercomprising calculating the blood flow rate from one of the upstreamsignal and the downstream signal.
 22. The method of claim 19, whereinone of the upstream signal and the downstream signal is in response tochanges of a blood parameter property including proteins, electricalimpedance, temperature, optical properties, sound velocity, blooddensity, blood chemistry and hematocrite.
 23. A medical device forprocessing a quantity of blood in a fluid path, comprising: (a) a filterhaving a filter blood volume; (b) an injection port in the fluid pathupstream of the filter for introducing a bolus into the fluid path; (c)a first blood parameter sensor intermediate the injection port andfilter for generating an upstream signal corresponding to passage of thebolus past the first blood parameter sensor; and (c) a second bloodparameter sensor downstream of the filter for generating a downstreamsignal corresponding to passage of the bolus past the second bloodparameter sensor; (d) means for determining a flow rate in the fluidpath; and (e) means for calculating the filter blood volume in responseto the downstream signal, the upstream signal and the flow rate.
 24. Themedical device of claim 23, wherein the means for determining a flowrate in the fluid path includes a flow rate sensor.
 25. The medicaldevice of claim 23, wherein the means for determining a flow rate in thefluid path determines the flow rate in response to the downstreamsignal.
 26. A method for the real time monitoring of a volume of bloodin a blood filter during operation of the filter, comprising: (a)measuring a blood parameter downstream of a blood side of the filter;(b) measuring a blood flow rate through the blood side of the filter;(c) changing a filtration rate to change the blood parameter; (d)calculating the blood volume from the change of the blood parameter andthe blood flow rate.
 27. The method of claim 26, further comprisingmaking changes in the blood parameter at a first and a second time. 28.The method of claim 26, further comprising measuring the blood parameterat a second time that is a steady state condition of the filter.
 29. Themethod of claim 26, further comprising measuring the blood flow ratewith a flow rate sensor.
 30. A medical device for processing a quantityof blood in a fluid path, comprising: (a) a filter having a blood sideand a dialysate side, the blood side defining a filter blood volume; (b)an injection port in the fluid path upstream of the filter forintroducing a bolus into the fluid path; (c) a blood parameter sensordownstream of the filter for generating a downstream signalcorresponding to passage of the bolus past the blood parameter sensor;(d) means for determining a flow rate in the fluid path; and (e) meansfor calculating the filter blood volume in response to the downstreamsignal, a change in a filtration rate and the flow rate.
 31. The medicaldevice of claim 30, wherein the means for determining a flow rate in thefluid path includes a flow rate sensor.
 32. The medical device of claim30, wherein the means for determining a flow rate in the fluid pathdetermines the flow rate in response to the downstream signal.
 33. Amethod for monitoring a volume of blood in a blood filter duringoperation of the filter, the blood filter having a blood side and adialysate side, comprising: (a) measuring a blood parameter in the bloodside downstream of the filter; (b) measuring a flow rate through thedialysate side; (c) changing a filtration rate to change the bloodparameter; and (d) calculating the volume of blood in the blood filterfrom the changed blood parameter and the measured flow rate through thedialysate side.
 34. The method of claim 33 wherein measuring a bloodparameter in the blood side downstream of the filter includes employinga dilution sensor.
 35. A medical device for processing a quantity ofblood in a fluid path, comprising: (a) a filter having a blood side anda dialysate side, the blood side defining a filter blood volume; (b) aninjection port in the fluid path upstream of the filter for introducinga bolus into the fluid path; (c) a blood parameter sensor downstream ofthe filter for generating a downstream signal corresponding to passageof the bolus past the blood parameter sensor; (d) means for determininga flow rate through the dialysate side of the filter; (e) a control forchanging the rate of filtration; and (f) means for calculating thevolume of blood in the filter from the changed blood parameter and thedetermined flow rate through the dialysate side.
 36. The medical deviceof claim 35, wherein the means for determining a flow rate through thedialysate side of the filter includes a flow rate sensor.
 37. A methodfor monitoring a volume of blood in a dialysis blood filter duringoperation of the filter, the blood filter having a blood side and adialysate side having a known volume, comprising: (a) changing aparameter of dialysate in the dialysate side upstream of the filter bypassing a diffusable bolus through the filter; (b) measuring a change ofdialysate downstream the filter due to passing the diffusable bolusthrough the filter; (c) measuring a flow rate in the dialysate side; and(d) calculating a blood volume in the blood side from the measuredchanges in dialysate parameter, the flow rate and the known volume ofthe dialysate side.
 38. A medical device for processing a quantity ofblood in a fluid path, comprising: (a) a filter having a blood side anda dialysate side, the blood side defining a filter blood volume; (b) aninjection port on the dialysate side upstream of the filter forintroducing a diffusable bolus to pass through the dialysate side of thefilter; (c) a blood parameter sensor on the dialysate side downstream ofthe filter for generating a downstream signal corresponding to passageof the bolus past the blood parameter sensor; (d) means for determininga flow rate through the dialysate side of the filter; and (e) means forcalculating a blood volume in the blood side from the measured changesin dialysate a parameter, the flow rate and a known volume of thedialysate side.
 39. The medical device of claim 38, wherein the meansfor determining a flow rate through the dialysate side of the filterincludes a flow rate sensor.
 40. A method for monitoring a change in avolume of blood in a dialysis blood filter during operation of thefilter, the blood filter having a blood side and a dialysate side,comprising: (a) measuring a blood parameter in the blood side downstreamof the filter; (b) changing a filtration rate to change the bloodparameter; (c) measuring the blood parameter in the blood sidedownstream of the filter after changing the filtration rate to obtain afirst value; (d) measuring a blood parameter in the blood sidedownstream of the filter; (e) changing a filtration rate to change theblood parameter; (f) measuring the blood parameter in the blood sidedownstream of the filter after changing the filtration rate to obtain asecond value; and (g) calculating the change in volume of blood in thedialysis blood filter from the first value and the second value.
 41. Amedical device for processing a quantity of blood in a fluid path,comprising: (a) a filter having a blood side and a dialysate side, theblood side defining a filter blood volume; (c) a blood parameter sensoron the blood side downstream of the filter for generating a downstreamsignal; (d) a control for changing a blood parameter to create a firstvalue and second value of the blood parameter; and (e) means forcalculating a change in the filter blood volume in response to a firstdownstream signal corresponding to the first value of the bloodparameter and a second downstream value corresponding to the secondvalue of the blood parameter.
 42. A method for monitoring a volume ofblood in a dialysis blood filter during operation of the filter, theblood filter having a blood side and a dialysate side, comprising: (a)injecting a non diffusable bolus upstream of the dialysate side; (b)injecting a diffusable bolus upstream of the dialysate side (c)measuring a dilution curve in response to the diffusable bolus and thenondiffusable bolus downstream of the filter in the dialysate site. (e)measuring a flow rate through the dialysate side; and (f) calculating ablood volume in the blood side corresponding to the dilution curve fromdiffusable bolus and nondiffusable bolus and the measured flow ratethrough the dialysate side.
 43. A method for monitoring a volume ofblood in a dialysis blood filter during operation of the filter, theblood filter having a blood side and a dialysate side, comprising: (a)injecting a bolus of a diffusable indicator and a non diffusableindicator upstream of the filter on the dialysate side; (c) measuring adilution curve from the diffusable indicator downstream of the filter ondialysate side; (d) measuring a dilution curve from the nondiffusableindicator downstream of the filter on the dialysate site; (e) measuringa flow rate through the dialysate side; and (f) calculating a bloodvolume in the blood side from the dilution curve from diffusableindicator, the dilution curve from nondiffusable indicator and themeasured flow rate through the dialysate side.
 44. A medical device forprocessing a quantity of blood in a fluid path, comprising: (a) a filterhaving a blood side and a dialysate side, the blood side defining afilter blood volume; (b) an injection port on the dialysate sideupstream of the filter for introducing one of a diffusable bolus and anon diffusable bolus to pass through the dialysate side of the filter;(c) a blood parameter sensor on the dialysate side downstream of thefilter for generating a downstream signal corresponding to passage ofthe bolus past the blood parameter sensor; (d) means for determining aflow rate through the dialysate side of the filter; and (e) means forcalculating a blood volume in the blood side corresponding to thedilution curve from diffusable bolus, the dilution curve from thenondiffusable bolus and the measured flow rate through the dialysateside.
 45. The medical device of claim 44, further comprising a firstinjection port and a second injection port on the dialysate sideupstream of the filter.
 46. The medical device of claim 44, wherein themeans for determining a flow rate through the dialysate side of thefilter includes a flow rate sensor.
 47. A method for monitoring a changein a volume of blood in a filter during operation of the filter,comprising: (a) obtaining a first blood parameter measurement downstreamof a blood side of the filter, the first blood parameter correspondingto a first filtration rate change; (b) obtaining a second bloodparameter measurement downstream of a blood side of the filter, thesecond blood parameter corresponding to a second filtration rate change;and (c) calculating a change in the volume of blood in the filter fromthe first blood parameter measurement and the second blood parametermeasurement.
 48. A medical device for processing a quantity of blood ina fluid path, comprising: (a) a filter having a blood side and adialysate side, the blood side defining a filter blood volume; (b) acontrol for changing a rate of filtration in the filter; (c) a bloodparameter sensor downstream of the filter for generating a firstdownstream signal corresponding to a first change in the rate offiltration and a second downstream signal corresponding to a secondchange in the rate of filtration; and (d) means for calculating thefilter blood volume in response to the first downstream signal and thesecond downstream signal.
 49. The method of claim 1, 7, 13, 19, 26, 33,37, 40, 42, 43 or 47, further comprising employing at least one of anultrasound velocity sensor, a sound velocity sensor, a temperaturesensor, an optical sensor, a density sensor, an electrical impedancesensor, a chemical sensor, and a physical blood property sensor.
 50. Themedical device of claim 5, 10, 16, 23, 30, 35, 38, 41, 44 or 48, furthercomprising at least one of an ultrasound velocity sensor, a soundvelocity sensor, a temperature sensor, an optical sensor, a densitysensor, an electrical impedance sensor, a chemical sensor, and aphysical blood property sensor.
 51. The method of claim 1, 7, 13, 19,26, 33, 37, 40, 42, 43 or 47, further comprising employing a feedbackloop for providing one of an alarm and a blood characteristicmodification in response to one of a measured blood volume and a changein blood volume.
 52. The medical device of claim 5, 10, 16, 23, 30, 35,38, 41, 44 or 48, further comprising a feedback loop for providing oneof an alarm and a blood characteristic modification in response to oneof a measured blood volume and a change in blood volume.